The overall objectives of this study are elucidating pharmacokinetic and pharmacodynamic parameters in methdadone maintainance patients. Among the goals are defining the "fast and slow" metabolizers and observing the effects of dose omission. Methadone dose, blood concentration and effect relationships in out-patients and in hospitalized patients were observed; during serial follow-ups marked fluctuations occurred in the 24 hour post dose plasma concentration of methadone in the majority of unselected patients. One interesting feature in several subjects was a considerable drop of plasma level after weekends, followed by some recovery during the week. On the other hand, the plasma concentration in selected reliable out- patients was quite stable; a planned omission of one daily dose in these subjects caused an approximately 50% drop from the preexisting level. We are continuing studies with out-patients to ascertain whether and which other factors besides irregular intake play a role in the plasma level fluctuations of methadone. Studies in hospitalized patients confirmed that during regular methadone intake stable 24 hour post dose plasma levels are maintained. The dose and plasma level ratios, however, varied considerably among subjects, suggesting individual differences in the rate of methadone metabolism and elimination. A planned omission of a dose again caused an approximately 50% drop in the plasma level followed by recovery in 1- 3 days after the resumption of previous doses.